UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

 

OFFICE OF CHEMICAL SAFETY AND

                                                                        
                      POLLUTION PREVENTION

MEMORANDUM

DATE:  	July 13, 2010

SUBJECT:	Isoxaben: Chronic Aggregate Dietary Exposure (Food and Drinking
Water) and Risk Assessment for the Section 3 Registration on Grapes and
Tree Nuts.

PC Code:  125851	DP Barcodes: D375246

Decision No.: 379577	Registration No.:  62719-LIN

Petition No.:  7F7222	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical Aggregate, Dietary	Case No.:  NA

TXR No.:  NA	CAS No.:  82558-50-7

MRID No.:  NA	40 CFR:  §180.xxx (not yet established)



		              				

REVIEWER:	Elizabeth Holman, Chemist

		Dennis McNeilly, Chemist

Risk Assessment Branch II  (RAB2)

Health Effects Division (HED; 7509P)

THROUGH:	Julie VanAlstine, MPH, Environmental Health Scientist

Douglas Dotson, Ph.D., Chemist

Dietary Exposure Science Advisory Council

Health Effects Division (HED; 7509P)

and

Richard Loranger, Ph.D., Branch Senior Scientist

Risk Assessment Branch II (RAB2)

Health Effects Division (HED; 7509P)

TO:		   Kathryn V. Montague, PM-23

		   Herbicide Branch

		   Registration Division (RD; 7505P)

Executive Summary

A chronic aggregate dietary risk assessment (food and drinking water)
was conducted using the Dietary Exposure Evaluation Model (DEEM-FCID,
Version 2.03), which uses food consumption data from the U.S. Department
of Agriculture (USDA’s) Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  The analysis was performed
to support a Section 3 registration for use of isoxaben
[N-[3-(1-ethyl-1-methylpropyl)-5-isoxazolyl]-2,6-dimethoxybenzamide] on
grapes and tree nuts.

Acute Dietary Exposure (Food and Drinking Water) Results and
Characterization

No appropriate endpoint attributable to a single dose was identified. 
As no acute dietary endpoint was identified, an acute exposure analysis
was not performed.

Chronic Dietary (Food and Drinking Water) Exposure Results and
Characterization

The chronic analysis is based on tolerance level residues and 100% crop
treated assumptions.  Default processing factors were used for grape
juice (1.2x), and grapes, raisin (4.3x).  The HED-recommended tolerance
level for each raw agricultural commodity (RAC) was entered as listed
below: 

 

Grape	0.01 ppm

Nut, tree, group 14	0.02 ppm

Pistachio	0.02 ppm

The general U.S. population and all population subgroups have risk
estimates that are well below HED’s level of concern (i.e., 100% of
the chronic population adjusted dose (cPAD)).  The most highly exposed
population subgroup is Infants <1 yr, which utilizes 17% of the cPAD. 
The general U.S. population utilizes 5.1% of the cPAD.

Cancer Dietary (Food and Drinking Water) Exposure Results and
Characterization

  SEQ CHAPTER \h \r 1 In accordance with EPA’s Final Guidelines for
Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review
Committee (CARC) classified isoxaben as having “Suggestive Evidence of
Carcinogenicity,” but concluded that quantification of carcinogenic
potential is not required.  The CARC determined that the cRfD is
protective of cancer effects.  As a result, a separate cancer dietary
exposure analysis was not performed.  Cancer risk from dietary exposure
to isoxaben is not of concern to HED.  

I.	Introduction

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide.  For acute and chronic assessments, the risk is
expressed as a percentage of a maximum acceptable dose (i.e., the dose
which HED has concluded will result in no unreasonable adverse health
effects).  This dose is referred to as the population adjusted dose
(PAD).  The PAD is equivalent to the point of departure (POD, NOAEL,
LOAEL, e.g.) divided by the required uncertainty or safety factors.

For acute and non-cancer chronic exposures, HED is concerned when
estimated dietary risk exceeds 100% of the PAD.  HED is generally
concerned when estimated cancer risk exceeds one in one million. 
References which discuss the acute and chronic risk assessments in more
detail are available on the EPA/pesticides web site:  “Available
Information on Assessing Exposure from Pesticides, A User’s Guide,”
6/21/2000, web link: 
http://www.epa.gov/fedrgstr/EPA-PEST/2000/July/Day-12/6061.pdf ;  or see
SOP 99.6 (8/20/99).



This is the first food use and first dietary risk assessment to be
conducted for isoxaben.  

II.	Residue Information

Isoxaben is a benzamide herbicide (Group 21) used for control of
broadleaf weeds.  Isoxaben reportedly acts via inhibition of cell wall
synthesis.  The herbicide is currently registered for non-food uses on
turf, ornamentals, non-bearing fruit and nut trees, and non-bearing
vineyards.

The petitioner has proposed a new Section 3 use on grapes, tree nuts,
and pistachios.  See Table 1 below for a summary of the HED-recommended
tolerances. 

Table 1.  Summary of HED- Recommended Tolerances for Proposed New Use

Commodity	 Recommended Tolerance (ppm)

Grape 	0.01

Nut tree, group 14 	0.02

Pistachio 	0.02



For grapes and tree nuts (including pistachio), isoxaben parent serves
as an adequate measure of misuse based on its percentage of the total
radioactive residues (TRR) in the metabolism studies and the residues
seen in crop field trials.  

HED is making the conservative assumption of 100% crop treated.

Processing Factors:

Conducted at 5x the proposed maximum seasonal application rate, the
submitted processing study on grapes showed residues <LOQ (0.01 ppm)
in/on all samples of grapes, raisins, and grape juice; therefore,
processing factors could not be calculated.  Therefore default
processing factors were used for grape juice and raisins (summarized in
Table 2).   

  SEQ CHAPTER \h \r 1 Table 2.	Summary of Processing Factors for
Isoxaben

RAC	Processed Commodity	Processing Factor (Default)

Grape	Grape juice	1.2x

	Raisins	 4.3x



III.  Drinking Water Data

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
following memorandum: “Tier I Drinking Water Assessment for the
Isoxaben Proposed New Use on Bearing Nut Trees and Vineyards” (341497,
C. Peck, 3/18/2010) and incorporated directly into this dietary
assessment.  Water residues were incorporated in the DEEM-FCID into the
food categories “water, direct, all sources” and “water, indirect,
all sources.”   

The estimated drinking water concentrations (EDWCs) are based on the
maximum proposed application rates specified in the product labels.  The
EDWCs for the human health risk assessment are presented in Table 3. 
Because isoxaben has a number of major degradates whose toxicity is
similar to that of isoxaben, a total toxic residue (TTR) approach was
used in the modeling.  The Residue of Concern Knowledge-based
Subcommittee (ROCKS) recommended that the drinking water assessment for
isoxaben include hydroxyisoxaben, dimethoxybenzamide,
methoxyphenylpyrimidinol, and AEM hexenoylisoxaben.  

 TC \l2 " 3.1	Hazard and Dose-Response 

The drinking water exposure assessment for isoxaben and total isoxaben
residues is based on modeling.  Estimated drinking water concentrations
for isoxaben and total isoxaben residues are shown in Table 3.  

The estimated drinking water concentrations (EDWC) were calculated using
a Tier I model for surface water (FQPA Index Reservoir Screening Tool or
FIRST) and a Tier I model for groundwater (Screening Concentration in
Ground Water or SCI-GROW).  The surface water values were higher than
the groundwater values in all scenarios.  Two sets of modeling runs were
completed: one set using the mobility estimates of the parent and one
set using mobility estimates derived from the isoxaben degradate study. 
RAB2 has selected the most conservative estimate in order to be
sufficiently protective of human health.  The maximum annual mean FIRST
EDWC in surface water (from the modeling of the isoxaben degradates) was
120 µg/L for ornamental use.  

Table 3. Tier I Estimated Drinking Water Concentrations (EDWCs)
resulting from applications of isoxaben on ornamentals and bearing nut
trees.

Drinking water source (model)	Use 

(modeled rate)	Chronic 

(µg/L)

Parent Kd Data

Surface water (FIRST)	Ornamental	54.7

Groundwater (SCIGROW)	Ornamental	2.13

Surface water (FIRST)	Bearing nut trees and vineyards	16.9

Groundwater (SCIGROW)	Bearing nut trees and vineyards	0.71

Degradate Kd Data

Surface water (FIRST)	Ornamental	120

Groundwater (SCIGROW)	Ornamental	43.6

Surface water (FIRST)	Bearing nut trees and vineyards	37.0

Groundwater (SCIGROW)	Bearing nut trees and vineyards	14.5



Monitoring Data

Isoxaben is not included as one of the analytes monitored in U.S.
surface and groundwater under the USGS’s National Water Quality
Assessment (NAWQA) program (  HYPERLINK "http://water.usgs.gov/nawqa" 
http://water.usgs.gov/nawqa ). There were no detections in six surface
water and sediment samples collected and analyzed for isoxaben by
California Department of Pesticide Regulation (CDPR) in 2006 in
Stanislaus County.

IV.	DEEM-FCID( Program and Consumption Information

An isoxaben chronic dietary exposure assessment was conducted using the
DEEM-FCID(, Version 2.03, which incorporates consumption data from
USDA’s CSFII, 1994-1996 and 1998.  The 1994-96, 98 data are based on
the reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (e.g., apple pie)
are linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events.  Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate. The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

V.	Toxicological Information

The Health Effects Division (HED) has evaluated the toxicology database
for isoxaben.  The RAB2 risk assessment team reviewed the toxicology
data for isoxaben with regard to the acute and chronic reference doses
and the toxicological endpoint selection.  Table 4 below provides a
summary of the doses and endpoints recommended for use in the dietary
exposure assessments.    SEQ CHAPTER \h \r 1 In accordance with EPA’s
Final Guidelines for Carcinogen Risk Assessment (March, 2005), the
Cancer Assessment Review Committee (CARC) classified isoxaben as having
“Suggestive Evidence of Carcinogenicity,” but concluded that
quantification of carcinogenic potential is not required.  The cRfD is
protective of cancer effects.  The FQPA safety factor was reduced to 1x
for all exposure scenarios.  

Table 4 Summary of Toxicological Doses and Endpoints for Isoxaben for
Use in Dietary Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary, General Population, including Infants, Children and
Females Age 13 to 49	Not required.  Appropriate endpoints for this risk
assessment were not identified.

Chronic Dietary (All Populations)	NOAEL= 5.0  mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x   	Chronic RfD = 0.05

mg/kg/day

cPAD = 0.05 mg/kg/day	Chronic oral toxicity/carcinogenicity in the rat

LOAEL = 50.7 mg/kg/day, based on renal toxicity in males.

Cancer (oral, dermal, inhalation)	Classification:  Suggestive Evidence
of Carcinogenic Potential, based on increased incidence of
hepatocellular adenomas in male and female mice.  A quantitative
assessment of cancer risk is not required.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  FQPA SF = FQPA Safety Factor.  PAD = population
adjusted dose (a = acute, c = chronic).  RfD = reference dose.  

VI.	Results/Discussion

As stated above, for acute and chronic assessments, HED is concerned
when dietary risk exceeds 100% of the PAD.  The DEEM-FCID( analysis
estimates the dietary exposure of the U.S. population and various
population subgroups.  The results reported in Table 5 are for the
general U.S. Population, all infants (<1 year old), children 1-2,
children 3-5, children 6-12, youth 13-19, females 13-49, adults 20-49,
and adults 50+ years.

Results of Acute Dietary (Food and Drinking Water) Exposure Analysis

No appropriate endpoint attributable to a single dose was identified. 
As no acute dietary endpoint was identified, an acute exposure analysis
was not performed.

Results of Chronic Dietary (Food and Drinking Water) Exposure Analysis

The summary table below lists the results of the chronic dietary
exposure analysis.  The chronic dietary risk estimates for the general
U.S. population utilized 5.1% of the cPAD.  The most highly exposed
population subgroup was all infants (<1 yr old), which utilized 17% of
the cPAD.  All population exposures are well below HED’s level of
concern.   



Table 5.  Summary of Dietary Exposure and Risk for Isoxaben1





Population Subgroup*	

Acute Dietary	

Chronic Dietary	

Cancer

	

Dietary Exposure (mg/kg/day)	

% aPAD	

Dietary Exposure

(mg/kg/day)	

% cPAD	

Dietary Exposure

(mg/kg/day)	

Risk

General U.S. Population	N/A

No acute dietary endpoint was identified	N/A	0.002536	5.1	

N/A	

N/A

All Infants (< 1 year old)

	0.008303	17



Children 1-2 years old

	0.003794	7.6



Children 3-5 years old

	0.003539	7.1



Children 6-12 years old

	0.002434	4.9



Youth 13-19 years old

	0.001832	3.7



Adults 20-49 years old

	0.002366	4.7



Adults 50+ years old

	0.002489	5.0



Females 13-49 years old

	0.002356	4.7



1The value for the highest exposed population in this chronic risk
assessment is bolded.  



VII.	Characterization of Inputs/Outputs

As the exposure estimates to all population subgroups were so low, it
was not necessary to make refinements to the chronic dietary analysis. 
If it had been necessary to refine the analysis, average field trial
values could have been used in place of tolerance level residues.  In
addition, estimates of percent crop treated could have been used.

VIII.	Conclusions

Based on very conservative assumptions, the chronic dietary risk
estimates are well below HED’s level of concern for the general U.S.
population and all population subgroups, including those comprised of
infants and children.  In addition, cancer risk from dietary exposure to
isoxaben is not of concern to HED (the cRfD is protective of cancer
effects).  Based on the conservative nature of the chronic dietary
endpoint and the drinking water assessment, exposure and risk to
isoxaben are not expected to be underestimated.  

IX.	List of Attachments

Attachment 1: Residue Input File for Chronic Analysis

Attachment 2: Results of Chronic Dietary Exposure Analysis

Attachment 1:  Isoxaben Residue Input File

Filename: C:\Documents and Settings\EHOLMAN\My
Documents\isoxaben0414.R98

Chemical: Isoxaben

RfD(Chronic): .05 mg/kg bw/day  NOEL(Chronic): 5 mg/kg bw/day

RfD(Acute): 0 mg/kg bw/day  NOEL(Acute):  0 mg/kg bw/day

Date created/last modified: 04-14-2010/17:33:53/8          Program ver.
2.03

------------------------------------------------------------------------
--------

  EPA    Crop                                   Def Res     Adj.Factors 
 Comment

  Code    Grp  Commodity Name                    (ppm)       #1    #2   

-------- ---- -------------------------------  ----------  ------ ------
 -------

95001750 O    Grape                              0.010000   1.000  1.000
 

95001760 O    Grape, juice                       0.010000   1.200  1.000
 

95001761 O    Grape, juice-babyfood              0.010000   1.200  1.000
 

95001770 O    Grape, leaves                      0.010000   1.000  1.000
 

95001780 O    Grape, raisin                      0.010000   4.300  1.000
 

95001790 O    Grape, wine and sherry             0.010000   1.000  1.000
 

86010000 O    Water, direct, all sources         0.120000   1.000  1.000
 

86020000 O    Water, indirect, all sources       0.120000   1.000  1.000
 

14000030 14   Almond                             0.020000   1.000  1.000
 

14000031 14   Almond-babyfood                    0.020000   1.000  1.000
 

14000040 14   Almond, oil                        0.020000   1.000  1.000
 

14000041 14   Almond, oil-babyfood               0.020000   1.000  1.000
 

14000590 14   Brazil nut                         0.020000   1.000  1.000
 

14000680 14   Butternut                          0.020000   1.000  1.000
 

14000810 14   Cashew                             0.020000   1.000  1.000
 

14000920 14   Chestnut                           0.020000   1.000  1.000
 

14001550 14   Filbert                            0.020000   1.000  1.000
 

14001560 14   Filbert, oil                       0.020000   1.000  1.000
 

14001850 14   Hickory nut                        0.020000   1.000  1.000
 

14002130 14   Macadamia nut                      0.020000   1.000  1.000
 

14002690 14   Pecan                              0.020000   1.000  1.000
 

14002820 14   Pistachio                          0.020000   1.000  1.000
 

14003910 14   Walnut                             0.020000   1.000  1.000
 Attachment 2:  Results of Isoxaben Chronic Dietary Exposure Analysis

U.S. Environmental Protection Agency                                
Ver. 2.00

DEEM-FCID Chronic analysis for ISOXABEN                         (1994-98
data)

Residue file name: C:\Documents and Settings\EHOLMAN\My
Documents\isoxaben0414.R98

                                                 Adjustment factor #2
NOT used.

Analysis Date 04-16-2010/16:15:54     Residue file dated:
04-14-2010/17:33:53/8

Reference dose (RfD, Chronic) = .05 mg/kg bw/day

========================================================================
=======

                    Total exposure by population subgroup

------------------------------------------------------------------------
-------

                                                    Total Exposure

                                        
-----------------------------------

          Population                         mg/kg             Percent
of   

           Subgroup                       body wt/day             Rfd   
   

--------------------------------------   -------------      
---------------

U.S. Population (total)                     0.002536                
5.1%

U.S. Population (spring season)             0.002514                
5.0%

U.S. Population (summer season)             0.002724                
5.4%

U.S. Population (autumn season)             0.002451                
4.9%

U.S. Population (winter season)             0.002452                
4.9%

Northeast region                            0.002315                
4.6%

Midwest region                              0.002564                
5.1%

Southern region                             0.002410                
4.8%

Western region                              0.002905                
5.8%

Hispanics                                   0.002876                
5.8%

Non-hispanic whites                         0.002475                
4.9%

Non-hispanic blacks                         0.002407                
4.8%

Non-hisp/non-white/non-black                0.003105                
6.2%

All infants (< 1 year)                      0.008303               
16.6%

Nursing infants                             0.003079                
6.2%

Non-nursing infants                         0.010285               
20.6%

Children 1-6  yrs                           0.003560                
7.1%

Children 7-12 yrs                           0.002306                
4.6%

Females 13-19 (not preg or nursing)         0.001784                
3.6%

Females 20+ (not preg or nursing)           0.002530                
5.1%

Females 13-50 yrs                           0.002452                
4.9%

Females 13+ (preg/not nursing)              0.002462                
4.9%

Females 13+ (nursing)                       0.003508                
7.0%

Males 13-19 yrs                             0.001864                
3.7%

Males 20+ yrs                               0.002270                
4.5%

Seniors 55+                                 0.002488                
5.0%

Children 1-2 yrs                            0.003794                
7.6%

Children 3-5 yrs                            0.003539                
7.1%

Children 6-12 yrs                           0.002434                
4.9%

Youth 13-19 yrs                             0.001832                
3.7%

Adults 20-49 yrs                            0.002366                
4.7%

Adults 50+ yrs                              0.002489                
5.0%

Females 13-49 yrs                           0.002356                
4.7%

Isoxaben	                                                 Dietary
Exposure Assessment                                         DP Barcode:
375246

PC Code: 125851		

	

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